In the U.S., bladder cancer—primarily urothelial cancer—is the fourth most common malignancy in men and the twelfth most common in women. In 2018, experts expect about 82,000 new cases to be diagnosed and 17,240 bladder cancer deaths (CA Cancer J Clin 2018;68(1):31-54). Approximately 25 percent of the new cases will be locally advanced muscle-invasive urothelial cancer (MIUC) or metastatic UC (mUC) (Lancet 2016:388(10061):2796-2810).
MIUC is known to have a high rate of progression to metastatic disease, and the most effective curative treatment is neoadjuvant chemotherapy with a platinum-based chemotherapy regimen followed by radical cystectomy (Eur Urol 2005;48(2):202-205; discussion 205-206). Despite this intervention, metastatic disease, which is incurable, often develops, leaving only 10-15 percent of these patients alive at 5 years (J Clin Oncol 2005;23(21):4602-4608; J Clin Oncol 2011;29(17):2432-2438).
In chemotherapy-naïve patients with mUC, platinum-based therapy is associated with a median overall survival (OS) of 9-15 months (J Clin Oncol 2005;23:4602-4608; J Clin Oncol 2012;30(2):191-199), but having undergone platinum-based therapy previously can reduce that outcome to only 5-7 months (J Clin Oncol 2009;27(27):4454-4461).
In addition, a significant percentage of patients who might benefit from first-line cisplatin-based chemotherapy are found to be ineligible because of poor performance status, impaired renal function, or one or more other comorbidities, while for others therapy is withheld because of the risk of toxicity (J Clin Oncol 2011;29(17):2432-2438; Ann Oncol 2014;25(Suppl 3):iii40-iii48; Eur J Cancer 2015;51(Suppl 3):S520-S521; NCCN. Clinical Practice Guidelines in Oncology: Bladder Cancer. V.2.; 2016).
The recent advent of immuno-oncology is beginning to change the treatment paradigm in this disease. Explaining how the immune system attacks tumor cells expressing tumor antigen bound to the major histocompatibility complex on an antigen-presenting cell, activating a T cell, which then infiltrates the tumor, dysregulating it to prevent autoimmunity, is complex and beyond the scope of this article. However, knowing for some time that tumor cells use the normal checkpoints in this process to evade immune destruction, researchers are now targeting this mechanism as an effective way to enlist the immune system in countering malignancy.
The currently available checkpoint inhibitors (CPIs) have produced significant and durable clinical responses in a variety of tumors. Drugs targeting the PD-1 or its ligand (PD-L1) have been the most thoroughly studied and have proved the most clinically viable CPIs.
Platinum-Refractory & Relapsed Urothelial Cancer
Platinum-based therapy remains the standard first-line treatment in advanced urothelial cancer, but since results from second-line chemotherapy have been so poor, it is not surprising that immunotherapy was first shown to have activity in disease refractory to platinum-containing drugs.
Atezolizumab, a monoclonal IgG1 antibody targeting PD-L1 and resulting in inhibition of the PD-1 receptor, was the first to show activity in mUC (Nature 2014;515(7528):558-562). This success led to IMvigor210, a single-arm, multicenter, phase II trial of atezolizumab in 310 patients with inoperable or metastatic urothelial cancer who had previously received cisplatin (cohort 2).
The overall response rate (ORR) was 16 percent, with 7 percent complete responses (CRs) in the entire cohort, but those with the highest PD-L1 activity had a 28 percent ORR, including 15 percent CRs. However, responses were seen in all groups, including those with no PD-L1 expression, some of whom achieved CRs. The median time to response was 2.1 months, but late responses were seen in some patients.
Most impressive was that in responding patients, the median duration of response (mDOR) had not been met at the time of the report (Lancet 2016;387(10031):1909-1920). Because of this study, the FDA granted accelerated approval to atezolizumab in 2016 for patients refractory to platinum therapy, making it the first new drug approved in the U.S. for advanced urothelial cancer since cisplatin.
Pembrolizumab, a monoclonal IgG4 antibody targeting the PD-1 receptor, was granted regular approval by the FDA in 2017 for patients with locally advanced or mUC who during or after cisplatin-based therapy have disease progression. The approval was based on the results of KEYNOTE-045, a phase III open-label, randomized trial of pembrolizumab versus second-line, single-agent chemotherapy (paclitaxel, docetaxel, or vinflunine) in 542 patients.
The difference in the median OS of 10.3 months versus 7.3 months in favor of pembrolizumab was statistically significant. As with atezolizumab, responding patients had not reached the mDOR, while in the chemotherapy group it was 4.4 months (N Engl J Med 2017;376(11):1015-1026).
In addition, avelumab, durvalumab, and nivolumab were granted accelerated approval as second-line therapy when disease progresses during or after a first-line regimen containing a platinum drug, as long as it is within 12 months of the platinum therapy (Lancet Oncol 2018;19:51-64; JAMA Oncol 2017;3(9):e172411; Lancet Oncol 2017;18(3):312-322).
Cisplatin-Ineligible Patients With Unresectable or Metastatic Urothelial Cancer
Unfortunately, many patients are ineligible for treatment with cisplatin-based regimens (J Clin Oncol 2011;29(17):2432-2438; Ann Oncol 2014;25(Suppl 3):iii40-iii48; Eur J Cancer 2015;51(Suppl 3):S520-S521; NCCN. Clinical Practice Guidelines in Oncology: Bladder Cancer. V.2.; 2016) and receive either carboplatin-based combinations (J Clin Oncol 2012;30(2):191-199) or nonplatinum regimens, which have inferior results (Ann Oncol 2016;27:449-454; Clin Genitourin Cancer 2017;15(1):23-30.e2).
Atezolizumab in this population was addressed in cohort 1 of IMvigor210 and reported separately in January 2017 (Lancet 2017;389(10064):67-76). In 119 treated patients, the ORR was 23 percent, with 9 percent CRs. With respect to PD-L1 activity, responses were seen in all groups, but there was a correlation between response and the degree of positivity. With a median follow-up of 17.2 months, the mDOR was not reached, confirming that the responses were durable. Furthermore, the median OS of 15.9 months compared quite favorably to responses in historical controls treated without cisplatin, and it aligned with responses of those on cisplatin-based chemotherapy.
Similarly, in KEYNOTE-052, a trial with 374 cisplatin-ineligible patients, pembrolizumab was shown to have a 24 percent ORR, with 5 percent CRs and a disease control rate of 47 percent. Responses were highest in patients with more than 10 percent positive PD-L1 activity, but again, responses were seen in all groups. Responses were durable, with the mDOR not being reached at the time investigators published their results (Lancet Oncol 2017;18(11):1483-1492). These trials led to regular FDA approval of both pembrolizumab and atezolizumab as first-line therapy in cisplatin-ineligible patients with unresectable or mUC.
In recent months, the FDA restricted use and revised labeling of atezolizumab and pembrolizumab in patients with locally advanced or metastatic urothelial cancer, citing decreased survival linked to the drugs in comparison with that of patients on platinum-based chemotherapy, specifically in patients who never received prior therapy and had low levels of PD-L1 expression. In a follow-up, it also required use of companion assays for determining PD-L1 expression (FDA Alerts; https://www.fda.gov/Drugs/DrugSafety/ucm608075.htm). Data monitoring committees in IMvigor130 and KEYNOTE-361, two ongoing trials, detected the survival differences in early reviews, and neither study now enrolls patients with low PD-L1 status to the monotherapy arms, according to the FDA.
First-Line Treatment in Patients Eligible for Platinum-Based Therapy
At present, apart from that for cisplatin-ineligible patients, no CPI has been approved for use as first-line therapy in advanced urothelial cancer. Based on the responses in cisplatin-ineligible patients and those seen in second-line therapy, CPIs as monotherapy, in combinations with chemotherapy or other novel agents, compared to chemotherapy, are actively being investigated. There are four trials under way.
As noted above, two of these trials are targets of the FDA alerts regarding CPI monotherapy. The IMvigor130 (NCT02807636) and KEYNOTE-361 (NCT02853305) trials investigate pembrolizumab or atezolizumab, respectively, as monotherapy or in combination with cisplatin or carboplatin plus gemcitabine versus chemotherapy alone. These are designed to evaluate the safety and efficacy of combining a CPI and chemotherapy versus single-agent CPI treatment or platinum-based chemotherapy. In addition, they will try to evaluate biomarkers, especially PD-L1, as effective predictors of response in subgroups.
The DANUBE trial (NCT02516241) is a phase III randomized study comparing durvalumab monotherapy with durvalumab plus tremelimumab, a CTLA-4 inhibitor, versus standard of care chemotherapy with cisplatin or carboplatin plus gemcitabine. In the CheckMate-901 trial (NCT03036098), investigators are using four arms: 1) investigational immunotherapy of nivolumab combined with ipilimumab, a CTLA-4 inhibitor; 2) standard care with gemcitabine and carboplatin with or without cisplatin; 3) investigational immunotherapy with nivolumab combined with gemcitabine and cisplatin; and 4) standard care with gemcitabine and cisplatin. These trials are designed to evaluate one or more CPIs with or without platinum-based therapy against standard platinum-based chemotherapy.
These four trials are active (two are still accruing patients) with completion for DANUBE anticipated in late 2019 and CheckMate-901 in 2022.
Adjuvant, Neoadjuvant & Maintenance Therapy
Patients who have undergone potentially curative therapy with cystectomy or bladder-sparing therapy with or without neoadjuvant therapy have no standard adjuvant treatment to improve outcome. Immunotherapy offers to fill this gap, and three active trials are under way.
IMvigor010, evaluating atezolizumab (NCT02450331); CheckMate 274, evaluating nivolumab (NCT02632409); and AMBASSADOR, evaluating pembrolizumab (NCT03244384), are designed for patients at high risk for recurrence after primary treatment in operable MIUC. Accrual on these trials is expected to be complete in late 2019 or early 2020.
Two trials have evaluated the role of CPI in neoadjuvant therapy. The PURE-01 trial reported data at the 2018 ASCO Annual Meeting on three cycles of pembrolizumab followed by cystectomy in patients with operable MIUC (J Clin Oncol 2018;36(Suppl):abstract 4507). Cystoscopy and radiographic evaluation after the three cycles was followed by dose-dense MVAC (methotrexate, vinblastine sulfate, doxorubicin hydrochloride, and cisplatin) if treatment failed. Pathologic CR was reported in 39.5 percent of patients, with five additional patients found at cystectomy not to have MIUC.
In the ABACUS trial, also first reported at ASCO's 2018 meeting, of 69 patients treated with two cycles of atezolizumab before cystectomy, 29 percent achieved a partial CR, and an additional 39 percent were downstaged to disease with muscle invasion (J Clin Oncol 2018;36(Suppl):abstract 4506). In neither of these trials was there any reported increase in operative morbidity or mortality, suggesting that this form of neoadjuvant therapy is both safe and effective. The next step will be to compare it with standard-of-care cisplatin-containing neoadjuvant therapy.
The remaining clinical role for CPI therapy is maintenance therapy following response to first-line chemotherapy for unresectable or metastatic UC. Two trials are addressing this: one with pembrolizumab (NCT02500121) and another with avelumab in JAVELIN Bladder 100 (NCT02603432). Both these studies are actively accruing patients, and results are expected in late 2019 or 2020.
The role of immunotherapy, primarily as demonstrated by PD-1 and PD-L1 inhibitors, is rapidly evolving, with physicians anticipating additional agents, including CTLA-4 inhibitors.
There are now five PD-1 or PD-L1 inhibitors that are FDA-approved second-line agents that are deployable following progression after chemotherapy in unresectable or metastatic UC. Two others are approved for first-line therapy in cisplatin-ineligible patients.
A note of caution has been raised recently by new FDA restrictions after trials showed a decrease in survival in patients with low PD-L1 activity. They were undergoing first-line CPI monotherapy and fared poorer than patients on standard chemotherapy in two ongoing studies. Active trials in the neoadjuvant, adjuvant, first-line cisplatin-eligible, and maintenance settings are under way, and data from them should begin to be available in the next few years.
Questions persist regarding using biomarkers to predict response to immunotherapy, and their use remains a promising but confusing area of investigation. Most of the available data involve assays for PD-1 or PD-L1 in tumor cells, immune cells, or both, using different targeted assays obtained at different times in the disease. Findings have been difficult to interpret. Though responses, including CRs, have been documented in patients with negative test results, most trials have shown that responses are higher with a positive assay, and in certain settings, the FDA is setting new restrictions on treatment based on findings of low levels of PD-L1.
Tumor mutational burden, microsatellite instability, DNA repair gene mutations, and genomic evaluation including luminal versus basal subtypes are some of the other biomarkers that show promise of reliably predicting which patients will be best served with immunotherapy versus chemotherapy and potentially who might benefit most from agent combinations.
The good news is that, after a long period of stagnation in treatment development to improve outcomes in MIUC, there now appears to be burgeoning array of new drugs that offer hope of not only prolonging life but also curing significantly more patients in the future.
DAVID TOPOLSKY, MD, is a Hematologist-Oncologist & Medical Oncologist at the Cancer Treatment Centers of America in Philadelphia.
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